ABSTRACT: Considering that genome-wide sequencing and multigene testing will be performed on a large scale in the future, the number of individuals with high-risk germ-line mutations will greatly increase. Our ultimate goal is to develop a long-lasting, cost-efficient, and technically simple approach that allows for the immuno-prophylaxis of breast and ovarian cancer in high-risk patients by a one-time intravenous intervention. In this proposal, using an in vivo hematopoietic stem cell (HSC) gene therapy approach, we plan to convert HSCs into Trojan Horses to express immune checkpoint inhibitor or chimeric antigen receptor genes inside the tumor. Our goal is to show that this approach will prevent cancer in genetic mouse models that develop spontaneous breast or ovarian cancer.